This research project encompasses a number of different approaches to both understand how current antitubercular chemotherapy works using the most modern technologies and to use this information to develop new and improved therapies and therapeutic approaches. These studies span experimental chemotherapy models in rodents and higher vertebrates through to clinical trials in humans. [unreadable] [unreadable] Individual projects within this framework are; (1) understanding the action of various agents in animal models of tuberculosis therapy, (2) correlating animal models of disease with the pathology and response to therapy observed in human TB patients, (3) understanding the development of drug resistance within patients undergoing chemotherapy, (4) understanding the molecular basis of the need for the extended duration of chemotherapy required in humans to achieve a sterile cure for tubersulosi. [unreadable] [unreadable] One important aspect of the project relies on the development of advanced animal models for predicting drug efficacy under conditions that exactly mimic those experienced by TB patients. In partnership with scientists at the University of Pittsburg section scientists have been exploring the microenvironment of tuberculosis in non-human primates infected with MTb. [unreadable] [unreadable] Section scientists have also been involved in understanding the mechanism of action of second-line antituberculars and the evolution of multidrug resistance in patients in South Korea. A Natural History clinical research protocol opened this year at the Masan National Tuberculosis Hospital in South Korea for Multidrug-resistant TB patients and has enrolled several hundred volunteers in an effort to understand factors that contribute to the development of this condition. In addition this patient cohort has allowed an examination of the occurence of XDR (eXtensively Drug Resistant) disease in patients that have failed chemotherapy completely. This analysis was performed in close collaboration with NIAID epidemiologists. [unreadable] [unreadable] A Phase II clinical trial of pimonidazole, a marker of hypoxic tissues that has been evaluated in several other animal models of disease, is about to open in South Korean patients undergoing elective resection surgery for drug-resistant tuberculosis following approval by the Korean FDA.[unreadable] [unreadable] As part of a consortium of scientists jointly funded by the Bill and Melinda Gates Foundation and the Wellcome trust under the Grand Challenges in Global Health Program, TBRS has also initiated a Phase II trial of metronidazole with an extensive investigation of surrogate drug efficacy endpoints in partnership with the Novartis Institute for Tropical Diseases in Singapore and scientists at the National University of Singapore. This study involves the use of modern structural and functional imaging technologies (CT and PET) in patients that have failed first-time chemotherapy.